The broad, long term objectives of this proposal are to understand synaptic interactions in the vertebrate retina in terms of neurotransmitter and neuromodulator actions. The vertebrate retina is ideally suited for studying synaptic interactions. The retina is an accessible part of the central nervous system, its cells are large and easily recorded from, and it can be stimulated physiologically with light. This research will focus on the actions of the bipolar cell transmitter, glutamate. Bipolar cells provide the excitatory input to ganglion cells, the output cells of the retina. At some retinal synapses the effects of neurotransmitters are not rigid, but plastic and under the control of neuromodulator substances. Therefore, the roles of the neuromodulator substances that might regulate the release of glutamate from bipolar cells and regulate the actions of glutamate at the ganglion cell, will be investigated. High resolution whole-cell patch recordings will be made from morphologically-identified neurons in the retinal slice, as sell as in isolation. Specific pharmacological agents will be utilized to determine both the extracellular and intracellular mechanisms by which transmitter and modulator substances act at specific neurons. To study the roles of glutamate in retinal information processing, synaptic inputs to bipolar and ganglion cells in the retinal slice will be elicited with light or by selectively stimulating presynaptic inputs. Synaptic interactions mediated by glutamate will be determined by using antagonists substances to block the actions of endogenously released glutamate. The effects of the glutamate receptor modulators, glycine and the polyamines, will be determined using pharmacological agents that act at their modulatory sites. By determining the cellular mechanisms and defining the synaptic pathways that regulate the excitatory input to ganglion cells, this study will provide a more complete understanding of how the retinal output to the brain is formed. The health relatedness of project. This study will lead to a more thorough understanding of two of the most fundamental process in retinal information processing, neurotransmission and its modulation. It is from this basis knowledge that important clinical strides from the treatment of retinal dysfunction will result. It is known that some types of neurodegeneration in the retina are mediate by endogenous glutamate. An understanding of the effects of glutamate on ganglion cells may be important in determining how anoxia- and ischemia-induced neuronal damage occur in the retina.